ABCA1 elevating compounds

Abstract

The present invention provides compounds useful for increasing cellular ATP binding cassette transporter ABCA1 production in mammals, and to methods of using such compounds in the treatment of coronary artery diseases, dyslipidiemias and metabolic syndrome. The invention also relates to methods for the preparation of such compounds, and to pharmaceutical compositions containing them.

1. A compound having the structure of Formula I: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  and R 2  are independently optionally substituted lower alkyl, optionally substituted aryl, optionally substituted alkenyl, optionally substituted heteroaryl, or optionally substituted heterocyclyl; or 
 R 1  and R 2  when taken together with the carbon atom to which they are attached represent a 5 or 6 membered carbocyclic or heterocyclic ring; 
 R 3  is hydrogen, hydroxyl, optionally substituted lower alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted lower alkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, cyano, halo, —SO 2 —NR 9 R 10 , or —C(O)R 11 , in which R 9  and R 10  are independently hydrogen, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, or may joint to form a 5 or 6 membered optionally substituted heterocyclic ring, and R 11  is —OH or optionally substituted lower alkoxy; 
 R 6  is hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, C(O)R 12 , or —S(O) 2 R 13 , in which R 12  is optionally substituted lower alkyl, lower alkoxy or —NR 14 R 15 , in which R 13 , R 14 , and R 15  are independently hydrogen, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl, or R 14  and R 15  may join to form a 5 or 6 membered optionally substituted heterocyclic ring; 
 R 20  is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, —SR 14 , —C(S)R 14 , —C(S)NR 14 R 15 , —S(O) 2 R 13 , or —S(O) 2 NR 9 R 10 ; and 
 X is oxygen, sulfur, —S(O)—, —S(O) 2 — or —NR 16 —, in which R 16  is hydrogen, optionally substituted lower alkyl, optionally substituted aryl, —C(O)R 12 , or —S(O) 2 R 13 . 
 
     
     
       2. The compound of  claim 1 , wherein X is oxygen. 
     
     
       3. The compound of  claim 2 , wherein R 1  and R 2  are both independently optionally substituted lower alkyl. 
     
     
       4. The compound of  claim 3 , wherein R 6  is hydrogen. 
     
     
       5. The compound of  claim 4 , wherein R 20  is optionally substituted heteroaryl. 
     
     
       6. The compound of  claim 5 , selected from the group consisting of:
 4-methoxy-7,7-dimethyl-9-(1,2,3,4-tetraazol-5-yl)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline; 
 10-(1H-1,2,3,4-tetraazol-5-yl)(12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline; 
 (12aS,6aR)-1-methoxy-7,7-dimethyl-9-(1,3-oxazol-5-yl)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline; 
 (12aS,6aR)-1-methoxy-7,7-dimethyl-9-(1,2,3,4-tetraazol-5-yl)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline; 
 (12aS,6aR)-1-methoxy-7,7-dimethyl-9-(1,2,3-thiadiazol-4-yl)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline; 
 1-methoxy-7,7-dimethyl-9-(4-methyl(1,2,4-triazol-3-yl))-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline; 
 ethyl 1-((6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)-5-methyl-1H-pyrazole-4-carboxylate; 
 1-((6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)-5 -methyl-1H-pyrazole-4-carboxylic acid; 
 2-((6aR,12aS)-1-fluoro-6a,7,12,12a-tetrahydro-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)oxazole-4-carboxylic acid; 
 ethyl 1-((6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)-1H-pyrazole-4-carboxylate; 
 1-((6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)-1H-pyrazole-4-carboxylic acid; 
 1-((6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)-N,N-dimethyl-1H-pyrazole-4-carboxamide; 
 1-((6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)l-1H-pyrazole-4-((1,1-dione-1,4-thiazaperhydroin-yl)methanone); 
 1-((6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)-5-methyl-1H-pyrazole-4-((4-ethanesulfonylpiperazin-1-yl)methanone); 
 1-((6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)1-5-methyl-1H-pyrazole-4-((1,1-dione-1,4-thiazaperhydroin-yl)methanone); 
 2-((6aR,12aS)-1-fluoro-6a,7,12,12a-tetrahydro-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)oxazole-(4-(4-ethanesulfonylpiperazin-1-yl)methanone); 
 2-((6aR,12aS)-1-fluoro-6a,7,12,12a-tetrahydro-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)oxazole-(4-(1,1-dione-1,4-thiazaperhydroin-yl)methanone); 
 1-((6aR,12aS)-6a,7,12,12a-tetrahydro-1-fluoro-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)-5-methyl-1H-pyrazole-4-((4-ethanesulfonylpiperazin-1-yl)methanone); 
 1-((6aR,12aS)-6a,7,12,12a-tetrahydro-1-fluoro-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)1-5-methyl-1H-pyrazole-4-((1,1-dione-1,4-thiazaperhydroin-yl)methanone); 
 2-((6aR,12aS)-6a,7, 12,12a-tetrahydro-4-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)oxazole-4-carboxylic acid; 
 2-((6aR,12aS)-1-methoxy-6a,7,12,12a-tetrahydro-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)oxazole-(4-(4-ethanesulfonylpiperazin-1-yl)methanone); and 
 2-((6aR,12aS)-1-methoxy-6a,7,12,12a-tetrahydro-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)oxazole-(4-(1,1-dione-1,4-thiazaperhydroin-yl)methanone). 
 
     
     
       7. The compound of  claim 4 , wherein R 20  is optionally substituted heterocycle. 
     
     
       8. The compound of  claim 7 , selected from the group consisting of:
 4-((6aS,12aR)-4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)-1,4-thiazaperhydroine-1,1-dione; 
 4-(4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)-1,4-thiazaperhydroine-1,1-dione; and 
 4-((12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)-1,4-thiazaperhydroine-1,1-dione. 
 
     
     
       9. The compound of  claim 4 , wherein R 20  is aryl. 
     
     
       10. The compound of  claim 9 , namely 9-(3-(2H-1,2,3,4-tetraazol-5-yl)phenyl)(12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline. 
     
     
       11. The compound of  claim 4 , wherein R 20  is —SR 14 , —S(O) 2 R 13 , —C(S)R 14 , or —C(S)NR 14 R 15 . 
     
     
       12. The compound of  claim 11 , selected from the group consisting of:
 amino(4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))methane-1-thione; 
 (12aS,6aR)-1-methoxy-7,7-dimethyl-9-methylthio-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline; 
 (6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-9-(methylsulfonyl)-6H-chromeno[4,3-b]quinoline; and; 
 (6aR,12aS)-9-(4-fluorophenylsulfonyl)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinoline; and 
 2-((6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-ylsulfonyl)acetic acid. 
 
     
     
       13. The compound of  claim 1 , wherein the 12a,6a ring juncture is cis. 
     
     
       14. The compound of  claim 1 , wherein the 12a,6a ring juncture is trans. 
     
     
       15. The compound of  claim 1 , wherein the 12a,6a ring juncture provides a single enantiomer. 
     
     
       16. A method of treating a disease state or condition in a mammal that is alleviable by treatment with an agent capable of increasing ABCA-1 expression, wherein the disease state or condition is coronary artery disease, atherosclerosis, or dyslipidemia, the method comprising administering to a mammal in need thereof a therapeutically effective dose of a compound of  claim 1 . 
     
     
       17. The method of  claim 16 , wherein the disease state or condition is coronary artery disease or atherosclerosis. 
     
     
       18. A method for elevating serum levels of HDL cholesterol in a mammal, comprising administering to a mammal in need thereof a therapeutically effective dose of a compound of  claim 1 . 
     
     
       19. A method for promoting cholesterol efflux from cells in a mammal, comprising administering to a mammal in need thereof a therapeutically effective dose of a compound of  claim 1 . 
     
     
       20. A pharmaceutical composition comprising at least one pharmaceutically acceptable excipient and a therapeutically effective amount of a compound of  claim 1 .